1. Field of the Invention
This invention relates to novel multibinding compounds (agents) that are H1 histamine receptor antagonists and pharmaceutical compositions comprising such compounds. Accordingly, the multibinding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of allergic diseases such as rhinitis, urticaria, asthma, anaphylaxis, and the like.
The following publications are cited in this application as superscript numbers:
1 Hypersensitivity-Type I. In: Immunology. Chapter 19. Roitt, I., Brostoff, J., Male, D., Gower Medical Publishing. London, New York. (1995).
2 Histamine H1-receptor antagonists. Burger""s Medicinal Chemistry and Drug Discovery. Fifth edition. Vol. 5: Wolff, M. E., Ed., John Wiley and Sons, Inc., (1997).
3 Hill, S. J. xe2x80x9cDistribution, Properties, and Functional Characterisics of three classes of histamine receptorxe2x80x9d. Pharmacological Reviews., 42(1):45 (1990).
4 Histamine, Bradykinin, and their antagonists. In: The PharmacologicalBasis of Therapeutics. Hardman, J. G., Limbird, L. E., Molinoff, P. B., Ruddon, R. W. and Gilman, A. G. Ed., Chapter 25, McGraw-Hill Co., New York (1996).
All of the above publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.
Asthma, rhinitis, urticara and anaphylaxis are common disorders that are the result of Type I hypersensitivity reactions1. Type I hypersensitivy reactions occur when antigens (allergens) stimulate the production of IgE antibodies by B lymphocytes1. The IgE, in turn binds to high affinity Fc receptors on the surface of tissue mast cells or blood basophils1. The binding of IgE to the Fc receptors stimulates a degranulation reaction by mast cells or blood basophils, in which chemical mediators, such as histamine are released1. The release of histamine causes a cascade of pathological sequela including the following2: 1) contraction of the smooth muscle of bronchi, which leads to obstruction of air flow to lungs; 2) relaxation of smooth muscle around in fine blood vessels, which causes vasodilation and decreases in blood pressure; 3) an increase in the permeability of the capillary walls and consequently the leakage of plasma components leading to tissue edema. The trilogy of effects of a hypersensitivity reaction result in pathologies associated with allergic diseases such as asthma, rhinitis, urticara, and anaphylaxis which are the cause of significant morbitity, and increasingly, mortality in humans2.
Histamine produces its pathological effects by binding to a receptor located on the membrane of cells in many tissues2. The receptors for histamine, which are part of a superfamily known as the G-protein coupled receptors (GPCRs), are seven transmembrane proteins2. Histamine receptors are further divided into subtypes, known as H1, H2 and H3. The type of histamine receptor expressed on cells is tissue specific3. Thus, H1 is found in smooth muscles of intestine, uterus, bronchi, urinary bladder, fine blood vessels and brain. H2 is expressed in stomach, smooth muscles of airway, and blood vessels of heart, and immunoreactive cells. H3 is expressed in brain and lung3. The pathological effects of histamine in hypersensitivity reactions appear primarily due to the interaction of histamine with the H1 receptor.
In order to prevent the pathological action of histamine a variety of drugs have been developed that interfere with the ability of histamine to bind to its receptor. Thus, drugs such as loratadine, terfenadine, diphenydramine, and cetirizeine, known as H1 receptor antagonists, prevent the binding of histamine to the cell and obviate the consequent synthesis and release of chemical mediators that produce the symptoms of allergy4. Unfortunately, these drugs do not selectively bind to H1 resulting in often severe side effects including myocardiopathies, sedation, and anticholinergic side effects. Thus there exists a need for drugs that bind with high affinity to H1 histamine receptors and provide potent, efficacious and long term effects effects.
The multibinding compounds of the present invention fulfill this need.
This invention is directed to novel multibinding compounds (agents) that are H1 histamine receptor antagonists and are therefore useful in the treatment and prevention of allergic diseases such as rhinitis, urticaria, asthma, anaphylaxis, and the like.
Accordingly, in one aspect this invention is directed to a multibinding compound comprising 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands is a H1 histamine receptor antagonist, and pharmaceutically acceptable salts thereof.
In second aspect, this invention provides a multibinding compound of Formula (I):
(L)p(X)qxe2x80x83xe2x80x83(I)
wherein:
p is an integer of from 2 to 10;
q is an integer of from 1 to 20;
each X is independently a linker;
each ligand, L, is, independently of each other, a H1 histamine receptor antagonist; and pharmaceutically acceptable salts thereof.
Preferably, q is less than p in the multibinding compounds of this invention.
More preferably, each ligand, L, that is a H1 histamine receptor antagonist is independently selected from a group consisting of:
(i) a compound of formula (a): 
wherein:
n is 0, 1, or 2;
Q is carbon or nitrogen;
R1 and R2 are independently selected from the group consisting of hydrogen, halo, alkyl, carboxy, and alkylcarboxy;
R3 is hydrogen or hydroxy;
R4 is a covalent bond linking (a) to a linker;
(b) a compound of formula (b): 
wherein:
xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 is an optional bond;
R5 is selected from the group consisting of hydrogen, halo, alkyl, carboxy, and alkylcarboxy; and
R6 is covalent bond linking (b) to a linker;
(c) a compound of formula (c): 
wherein:
n1 is 1 or 2;
R7 is -(alkylene)xe2x80x94Oxe2x80x94R9 where R9 is alkyl; and
R8 is a covalent bond linking the ligand to a linker;
(d) a compound of formula (d): 
wherein:
A is nitrogen or oxygen;
R10 is hydrogen or halo; and
R11 is a covalent bond linking the ligand to a linker; and
(e) a compound of formula (e): 
wherein:
R12 is hydrogen or halo;
R13 is alkyl; and
R14 is a covalent bond linking the ligand to a linker; and pharmaceutically acceptable salts thereof.
Even more preferably, each linker, X, in the multibinding compound of Formula (I) independently has the formula:
xe2x80x94Xaxe2x80x94Zxe2x80x94(Yaxe2x80x94Z)mxe2x80x94Xaxe2x80x94
wherein:
m is an integer of from 0 to 20;
Xa at each separate occurrence is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NRxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NRxe2x80x94, xe2x80x94C(S), xe2x80x94C(S)Oxe2x80x94, xe2x80x94C(S)NRxe2x80x94 or a covalent bond where R is as defined below;
Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
each Ya at each separate occurrence is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94NRxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94C(O)NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2C(O)xe2x80x94, xe2x80x94NRxe2x80x2C(O)NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2C(S)NRxe2x80x2xe2x80x94, xe2x80x94C(xe2x95x90NRxe2x80x2)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(xe2x95x90NRxe2x80x2)xe2x80x94, xe2x80x94OC(O)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Nxe2x95x90C(Xa)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(Xa)xe2x95x90Nxe2x80x94, xe2x80x94P(O)(ORxe2x80x2)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94P(O)(ORxe2x80x2)xe2x80x94, xe2x80x94S(O)nCRxe2x80x2Rxe2x80x3xe2x80x94, xe2x80x94S(O)nxe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94S(O)nxe2x80x94, xe2x80x94Sxe2x80x94Sxe2x80x94, and a covalent bond; where n is 0, 1 or 2; and R, Rxe2x80x2 and Rxe2x80x3 at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic provided that at least one of Xa, Z, and Ya is not a covalent bond.
In a third aspect, this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands is a H1 histamine receptor antagonist, and pharmaceutically acceptable salts thereof.
Preferably the pharmaceutical composition comprises a compound of Formula (I):
(L)p(X)qxe2x80x83xe2x80x83(I)
wherein:
p is an integer of from 2 to 10;
q is an integer of from 1 to 20;
each X is independently a linker;
each ligand, L, is, independently of each other, a H1 histamine receptor antagonist; and pharmaceutically acceptable salts thereof.
Even more preferably, each linker, X, in the multibinding compound of Formula (I) independently has the formula:
xe2x80x94Xaxe2x80x94Zxe2x80x94(Yaxe2x80x94Z)mxe2x80x94Xaxe2x80x94
wherein:
m is an integer of from 0 to 20;
Xa at each separate occurrence is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NRxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NRxe2x80x94, xe2x80x94C(S), xe2x80x94C(S)Oxe2x80x94, xe2x80x94C(S)NRxe2x80x94 or a covalent bond where R is as defined below;
Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
each Ya at each separate occurrence is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94NRxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94C(O)NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2C(O)xe2x80x94, xe2x80x94NRxe2x80x2C(O)NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2C(S)NRxe2x80x2xe2x80x94, xe2x80x94C(xe2x95x90NRxe2x80x2)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(xe2x95x90NRxe2x80x2)xe2x80x94, xe2x80x94OC(O)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Nxe2x95x90C(Xa)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2C(Xa)xe2x95x90Nxe2x80x94, xe2x80x94P(O)(ORxe2x80x2)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94P(O)(ORxe2x80x2)xe2x80x94, xe2x80x94S(O)nCRxe2x80x2Rxe2x80x3xe2x80x94, xe2x80x94S(O)nxe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94S(O)nxe2x80x94, xe2x80x94Sxe2x80x94Sxe2x80x94, and a covalent bond; where n is 0, 1 or 2; and R, Rxe2x80x2 and Rxe2x80x3 at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic provided that at least one of Xa, Z, and Ya is not a covalent bond.
In a fourth aspect, this invention is directed to a method for treating diseases mediated by a H1 histamine receptor in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands is a H1 histamine receptor antagonist, and pharmaceutically acceptable salts thereof.
In a fifth aspect, this invention is directed to general synthetic methods for generating large libraries of diverse multimeric compounds which multimeric compounds are candidates for possessing multibinding properties for H1 histamine receptor. The diverse multimeric compound libraries provided by this invention are synthesized by combining a linker or linkers with a ligand or ligands to provide for a library of multimeric compounds wherein the linker and ligand each have complementary functional groups permitting covalent linkage. The library of linkers is preferably selected to have diverse properties such as valency, linker length, linker geometry and rigidity, hydrophilicity or hydrophobicity, amphiphilicity, acidity, basicity and polarization. The library of ligands is preferably selected to have diverse attachment points on the same ligand, different functional groups at the same site of otherwise the same ligand, and the like.
In a sixth aspect, this invention is directed to libraries of diverse multimeric compounds which multimeric compounds are candidates for possessing multibinding properties for H1 histamine receptor. These libraries are prepared via the methods described above and permit the rapid and efficient evaluation of what molecular constraints impart multibinding properties to a ligand or a class of ligands targeting a receptor. Accordingly, in one of its method aspects, this invention is directed to a method for identifying multimeric ligand compounds possessing multibinding properties for H1 histamine receptor which method comprises:
(a) identifying a ligand or a mixture of ligands wherein each ligand contains at least one reactive functionality;
(b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand;
(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; and
(d) assaying the multimeric ligand compounds produced in (c) above to identify multimeric ligand compounds possessing multibinding properties for H1 histamine receptor.
In another of its method aspects, this invention is directed to a method for identifying multimeric ligand compounds possessing multibinding properties for H1 histamine receptor which method comprises:
(a) identifying a library of ligands wherein each ligand contains at least one reactive functionality;
(b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand;
(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; and
(d) assaying the multimeric ligand compounds produced in (c) above to identify multimeric ligand compounds possessing multibinding properties for H1 histamine receptor.
The preparation of the multimeric ligand compound library is achieved by either the sequential or concurrent combination of the two or more stoichiometric equivalents of the ligands identified in (a) with the linkers identified in (b). Sequential addition is preferred when a mixture of different ligands is employed to ensure heterodimeric or multimeric compounds are prepared. Concurrent addition of the ligands occurs when at least a portion of the multimer compounds prepared are homomultimeric compounds.
The assay protocols recited in (d) can be conducted on the multimeric ligand compound library produced in (c) above, or preferably, each member of the library is isolated by preparative liquid chromatography mass spectrometry (LCMS).
In one of its composition aspects, this invention is directed to a library of multimeric ligand compounds which may possess multivalent properties for H1 histamine receptor which library is prepared by the method comprising:
(a) identifying a ligand or a mixture of ligands wherein each ligand contains at least one reactive functionality;
(b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and
(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands.
In another of its composition aspects, this invention is directed to a library of multimeric ligand compounds which may possess multivalent properties for H1 histamine receptor which library is prepared by the method comprising:
(a) identifying a library of ligands wherein each ligand contains at least one reactive functionality;
(b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and
(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands.
In a preferred embodiment, the library of linkers employed in either the methods or the library aspects of this invention is selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acidic linkers, basic linkers, linkers of different polarization and/or polarizability, and amphiphilic linkers. For example, in one embodiment, each of the linkers in the linker library may comprise linkers of different chain length and/or having different complementary reactive groups. Such linker lengths can preferably range from about 2 to 100 xc3x85.
In another preferred embodiment, the ligand or mixture of ligands is selected to have reactive functionality at different sites on said ligands in order to provide for a range of orientations of said ligand on said multimeric ligand compounds. Such reactive functionality includes, by way of example, carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, pseudohalides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides, boronates, and precursors thereof. It is understood, of course, that the reactive functionality on the ligand is selected to be complementary to at least one of the reactive groups on the linker so that a covalent linkage can be formed between the linker and the ligand.
In other embodiments, the multimeric ligand compound is homomeric (i.e., each of the ligands is the same, although it may be attached at different points) or heteromeric (i.e., at least one of the ligands is different from the other ligands).
In addition to the combinatorial methods described herein, this invention provides for an iterative process for rationally evaluating what molecular constraints impart multibinding properties to a class of multimeric compounds or ligands targeting a receptor. Specifically, this method aspect is directed to a method for identifying multimeric ligand compounds possessing multibinding properties for H1 histamine receptor which method comprises:
(a) preparing a first collection or iteration of multimeric compounds which is prepared by contacting at least two stoichiometric equivalents of the ligand or mixture of ligands which target a receptor with a linker or mixture of linkers wherein said ligand or mixture of ligands comprises at least one reactive functionality and said linker or mixture of linkers comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand wherein said contacting is conducted under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands;
(b) assaying said first collection or iteration of multimeric compounds to assess which if any of said multimeric compounds possess multibinding properties for H1 histamine receptor;
(c) repeating the process of (a) and (b) above until at least one multimeric compound is found to possess multibinding properties for H1 histamine receptor;
(d) evaluating what molecular constraints imparted multibinding properties to the multimeric compound or compounds found in the first iteration recited in (a)-(c) above;
(e) creating a second collection or iteration of multimeric compounds which elaborates upon the particular molecular constraints imparting multibinding properties to the multimeric compound or compounds found in said first iteration;
(f) evaluating what molecular constraints imparted enhanced multibinding properties to the multimeric compound or compounds found in the second collection or iteration recited in (e) above;
(g) optionally repeating steps (e) and (f) to further elaborate upon said molecular constraints.
Preferably, steps (e) and (f) are repeated at least two times, more preferably at from 2-50 times, even more preferably from 3 to 50 times, and still more preferably at least 5-50 times.